Stable galenic preparations comprising a benzimidazol and method for the production thereof

ABSTRACT

The invention relates to a novel benzimidazole formulation and to a process for its production. The benzimidazole formulation comprises a layer comprising the benzimidazole compound together with an acidic reacting compound.

[0001] The invention relates to a novel pharmaceutical formulation of abenzimidazole, in particular of omeprazole or of a similar compound,which is stable although it contains no alkaline reacting compound but,on the contrary, an acidic reacting compound in contact with thebenzimidazole. The invention also relates to a process for theproduction of such a formulation.

[0002] It is generally assumed that benzimidazoles such as omeprazoleare unstable in an acidic environment and that, for this reason,pharmaceutical formulations comprising such a benzimidazole ought tocomprise an alkaline reacting compound. One example of such aformulation is described in EP-A 0 247 983.

[0003] It is possible by combining the benzimidazoles with a sufficientquantity of alkaline reacting compound to obtain pharmaceuticalformulations having quite good stability. However, pharmaceuticalformulations of this type have intrinsic problems. For example, acidicgroups are present in the enteric coating of the formulations and areable to react with the alkaline reacting compound of the core. Whereasit is well known to separate the alkaline reacting core from the entericcoating by an intermediate layer, great care must be applied during theproduction of such pharmaceutical formulations in order to adjust thethickness and nature of the intermediate layer and the nature of theenteric coating to the alkalinity of the core so that a pharmaceuticalformulation with adequate stability and good bioavailability isobtained. Problems of this type are discussed, for example, in example 1of EP-A 0 247 983.

[0004] Some formulations in which the benzimidazole is not combined withan alkaline reacting compound have recently been developed. One exampleof such a development is described in U.S. Pat. No. 5,626,875,corresponding to EP-A 0 773 025. This publication discloses aformulation comprising

[0005] an inert core,

[0006] which is coated with a first layer which compries thebenzimidazole together with a water-soluble polymer,

[0007] a further layer comprising a water-soluble polymer and

[0008] an enteric coating.

[0009] In the examples of this publication, the benzimidazole isformulated with excipients which are generally regarded as inert, suchas, for example, talc. Talc in pharmaceutical quality may, however,contain impurities, and a pH of more than 7 is often measured in asuspension of talc in water (ISFET technique for phenol red indicator).

[0010] Several recently developed omeprazole-containing pharmaceuticalscombine omeprazole with a specific stabilizer in order to increase thestability of the composition, such as, for example, mannitol (EP-A 646006), TiO₂ (WO 96/37195) or cyclodextrins (WO 98/40069) or amino acids.However, it would be desirable to have available anomeprazole-containing pharmaceutical which is sufficiently stablewithout such a stabilizer.

[0011] There is a need for pharmaceuticals which comprise benzimidazolecompounds and, in particular, omeprazole or a similar compound as activeingredient, which have an excellent stability combined with goodbioavailability, and which do not show the problems and disadvantages ofsome prior art pharmaceuticals.

[0012] The present invention is based on the unexpected finding that thebenzimidazoles which have been regarded as very acid-labile in fact havean excellent stability when they are formulated together with a compoundwhich provides a pH of less than 7 if they are brought into contact withsufficient water in order to measure a pH (acidic reacting compound,acidic substance).

[0013] The invention thus provides a stable oral pharmaceutical whichcomprises a benzimidazole compound of the formula I

[0014] in which R1 is hydrogen, methoxy or difluoromethoxy, R2 ishydrogen, methyl or methoxy, R3 is methoxy, 2,2,2-trifluoroethoxy or3-methoxypropoxy, and R4 is hydrogen, methyl or methoxy, comprising:

[0015] (a) an inert core,

[0016] (b) thereon an active ingredient layer which comprises thebenzimidazole compound of the formula I mixed with an acidic reactingcompound and, where appropriate, pharmaceutically acceptable adjuvants,

[0017] (c) at least one inert layer and

[0018] (d) an outer layer which is applied to the inert layer and whichcomprises an enteric coating.

[0019] The invention also provides a process for producing thepharmaceuticals of the invention, which comprises the following steps:

[0020] (i) preparation of an inert core

[0021] (ii) coating of the inert core with a benzimidazole layer,

[0022] (iii) application of one or more inert layers

[0023] (iv) application of the enteric coating.

[0024] The benzimidazoles of the formula I are generally known aseffective inhibitors of gastric acid secretion. Typical examples of suchbenzimidazole compounds are omeprazole, lanzoprazole and pantoprazole.Most preference is given to omeprazole.

[0025] The inert core is preferably a known sugar/starch. This inertcore is coated with the benzimidazole layer. The benzimidazole layercomprises the active ingredient, the benzimidazole, in combination withthe acidic reacting compound. Pharmaceutically acceptable excipients maylikewise be present. The benzimidazole layer will generally comprise awater-soluble polymer (which is preferably non-alkaline) as binder,which is explained hereinafter.

[0026] The benzimidazole layer is coated with the inert coating whichseparates the first coating which comprises the benzimidazole, and theenteric coating. The inert coating generally comprises a water-solublepolymer and, where appropriate, other pharmaceutically acceptableexcipients.

[0027] It is preferred for the pH of an aqueous suspension or solutionobtained from the inert coating to be about 7. If two inert coatings arepresent, the pH of an aqueous suspension or solution of the first inertcoating is preferably lower than the pH of an aqueous suspension orsolution of the second inert coating.

[0028] It is preferred for at least two inert coatings (or layers;“layer” and “coating” is used synonymously in this description) to bepresent. The first inert coating generally comprises a water-solublepolymer, which is preferably non-alkaline, where appropriate an acidicreacting compound and, where appropriate, pharmaceutically acceptableexcipients. The second inert coating, which is applied between the firstinert coating and the enteric coating, generally comprises awater-soluble polymer, which is preferably non-alkaline, whereappropriate an acidic reacting compound and, where appropriate,pharmaceutically acceptable excipients. The second inert coating and thefirst inert coating preferably have different compositions.

[0029] The first inert coating (if present) serves as barrier betweenthe active benzimidazole layer and the second inert coating, which maycomprise ingredients which ought not to come into contact with thebenzimidazole layer. This first layer normally comprises a water-solublepolymer, preferably an acidic reacting compound and conventionalexcipients such as, for example, a lubricant. Polyethylene/polypropyleneglycol, known as poloxamer, is preferred as lubricant.

[0030] The second inert layer serves as intermediate layer between theenteric coating and the inert part of the preparation. It normallycomprises a water-soluble polymer and is ordinarily free of the acidicreacting compound (but may comprise the latter). It may furthermorecomprise conventional excipients such as talc and pigments, for exampletitanium dioxide.

[0031] If only one inert layer is present, this inert layer ordinarilyhas the same composition as the second inert layer described above.

[0032] The enteric coating serves as conventional enteric coating. Itcomprises conventional enteric substances known in the prior art, suchas cellulose phthalates and copolymers of the methacrylic acid type, forexample methacrylic acid/alkyl (meth)acrylate copolymers, which aresold, for example, under the name Eudragit®. A methyl radical and anethyl radical are preferred as alkyl radical.

[0033] The methacrylic acid type C copolymer complying with the USpharmacopeia is preferred. The product Eudragit L30D55 is particularlypreferred. A preferred polymer is a copolymer based on methacrylic acidand ethyl acrylate. The formula is as follows:

[0034] The ratio of free carboxyl groups to esters groups is preferablyabout 1:1. The average molecular weight is, for example, about 250,000.

[0035] A copolymer of this type will dissolve easily at pH values above5.5 to form salts.

[0036] Triethyl citrate and/or polyethylene glycol or similar compoundscan be used as plasticizers in the enteric coating. Talc may also bepresent. Other conventional excipients may also be present.

[0037] There are no special restrictions on the acidic reacting compoundpresent in the pharmaceuticals of the present invention. The acidicreacting compound is defined by providing a pH of less than 7 when it issuspended or dissolved in water.

[0038] In particular, the aqueous mixture used for coating andcomprising the benzimidazole and the acidic reacting compound ought tohave a pH of less than 7, preferably a pH in the range from 6.5 to 6.95,more preferably in the range from 6.6 to 6.95.

[0039] Accordingly, the layer which comprises omeprazole and the acidicreacting compound ought to provide a pH of less than 7 when it issuspended in water. An amount of 5 to 50 mg of the layer material,suspended in 100 mg of water, ought preferably to provide a pH in therange from 6.5 to 6.95, preferably from 6.6 to 6.95. The pH measurementsought preferably to take place immediately after the layer material hasbeen suspended in water. “Immediately” means in this connection within30 minutes, preferably within 5 minutes, after the material has beenadded to the water. It may be advantageous for practical reasons tomeasure the pH in a solution or suspension comprising the inert coretogether with the benzimidazole-containing layer. If the measurement iscarried out in the presence of the inert core, it is particularlyimportant for the measurement to be carried out immediately (preferablyas soon as possible) after the material has been placed in the water, inorder to avoid the risk of core material dissolving and influencing thepH. In particular, the core ought not to be broken up, so that the corematerial dissolves as slowly as possible.

[0040] If the inert coating comprises the acidic reacting compound, thepH of a solution or suspension of the inert coating ought to be lessthan 7; 5 to 50 mg of the coating material, suspended or dissolved in100 mg of water, ought preferably to provide a pH in the range from 6.5to 6.95, more preferably in the range from 6.6 to 6.95.

[0041] It is immaterial how the pH is measured, with preference for theknown ISFET technology using an ISFET electrode. Unless indicatedotherwise, pH measurements referred to in this description were doneusing ISFET technology at a temperature of 25° C.

[0042] The acidic reacting compound is preferably sodium dihydrogenphosphate (NaH₂PO₄) with which the best results in relation to stabilitycan be achieved. The amount of the acidic reacting compound isdetermined by the desired pH.

[0043] The acidic reacting compound is necessarily present in the layerwhich comprises the benzimidazole and is preferably present in the inertlayer. If two inert layers are present (preferred embodiment), theacidic reacting compound is preferably present in the first inert layer,while it is preferably absent from the second inert layer.

[0044] The water-soluble polymer, which is generally present in thebenzimidazole layer and in the inert layer(s), acts as a binder and maybe any polymer known to be soluble in water or rapidly disintegrating inwater. It is possible to use the same water-soluble polymer in alllayers in which it is present, or to use different water-solublepolymers in different layers. Preferred water-soluble polymers arenon-alkaline water-soluble polymers, and hydroxypropylmethylcelluloseand hydroxypropylcellulose are particularly preferred.

[0045] Conventional pharmaceutically acceptable excipients known to theskilled worker may be present in any of the layers of thepharmaceutical. These excipients preferably provide a pH of about 7 (forexample 5 to 9) in aqueous solution or suspension. The nature andquantity of these excipients can easily be determined by a skilledworker on the basis of his general expert knowledge.

[0046] Unless otherwise stated, the excipients comprise conventionalbinders, plasticizers, colorants, pigments such as titanium dioxide,talc and other known excipients.

[0047] It is unnecessary with the present invention for thebenzimidazole-containing layer to comprise a specific stabilizer for thebenzimidazole as described for several prior art pharmaceuticals, suchas mannitol (EP-A 646 006), TiO₂ (WO 96/37195) or cyclodextrins (WO98/40069) or amino acids. On the contrary, the benzimidazole-containinglayer preferably comprises only the benzimidazole, the binder and theacidic reacting compound.

[0048] The particularly preferred pharmaceutical of the presentinvention is a pellet formulation comprising

[0049] (a) an inert core which is a sugar/starch core,

[0050] (b) coated with a mixture of omeprazole,hydroxypropylmethylcellulose and sufficient sodium dihydrogen phosphatefor 5 to 50 mg of the coating material, suspended or dissolved in 100 mgof water, to provide a pH in the range from 6.5 to 6.95, preferably 6.6to 6.95,

[0051] (c) a first inert coating applied to the omeprazole-containinglayer, where the first inert coating consists essentially ofhydroxypropylmethylcellulose, polyethylene/-polypropylene glycol andsufficient sodium dihydrogen phosphate for 5 to 50 mg of coatingmaterial in 100 mg of water to provide a pH in the range from 6.5 to6.95, preferably in the range from 6.6 to 6.95,

[0052] (d) a second inert coating applied to the first inert coating,where the second inert coating consists essentially ofhydroxypropylmethyl-cellulose, talc and titanium dioxide, and

[0053] (e) an outer layer applied to the second inert coating,consisting essentially of methacrylic acid/alkyl (meth)acrylatecopolymer, triethyl citrate and talc.

[0054] It is likewise preferred for a pellet which has only the inertcore and the benzimidazole-containing coating to provide a pH in therange from 6.6 to 6.95 when it is suspended in 4 μl of deionized water.If two or more inert layers are present, it is likewise preferred for apellet which has only the inert core, the benzimidazole-containingcoating and the first inert coating to provide a pH in the range from6.6 to 6.95 when it is suspended in 4 μl of deionized water. It is inturn preferred for the pH measurement to be carried out immediatelyafter the material has been added to the water in order to minimize apossible effect of the inert core (within 30 minutes, preferably within5 minutes, after the material has been introduced into the water).

[0055] The pharmaceuticals of the present invention can be produced byknown processes. The coating steps are preferably carried out in afluidized bed coating apparatus. The pharmaceuticals of the presentinvention are in the form of pellets, and the final dosage formadministered to the patient is a capsule comprising the pellets. Analternative possibility is also to compress the pellets to a tablet.

[0056] It is preferred for drying steps to be carried out between thecoating steps, but this is not absolutely necessary. If a drying step iscarried out, it is unnecessary to interrupt the fluidized bed process(that is to say the drying step can be carried out in the fluidizedbed), but obviously the spraying must be stopped during the drying step.If a drying step is carried out, it lasts about 10 to 20 minutes.

[0057] The following examples illustrate the invention but are notrestrictive.

EXAMPLE 1

[0058] A dispersion is prepared from 140 g of deionized water, 20 g ofomeprazole and 15 g of hydroxypropylmethyl-cellulose. The pH of thisdispersion is adjusted to a pH of 6.65 with an aqueous 0.5 M sodiumdihydrogen phosphate solution. The pH is measured by an ISFET electrode.140 g of neutral pellets are coated in a fluidized bed coating apparatuswith the suspension prepared in this way.

[0059] A suspension for the inert coating is prepared by dispersing 125g of deionized water, 3 g of titanium dioxide, 5 g of talc and 15 g ofhydroxypropylmethyl-cellulose. The pellets with the omeprazole coatingare coated with this suspension in a fluidized bed coating apparatus.

[0060] The pellets produced in this way are coated in a known mannerwith an enteric coating. The suspension of the enteric coating isprepared from 30 g of methacrylic acid copolymer type C (complying withUS pharmacopeia), 12 g of talc, 4.5 g of triethyl citrate and 95.0 g ofdeionized water. A fluidized bed coating apparatus is again used.

[0061] The pellets obtained in this way are stable and provide excellentbioavailability.

EXAMPLE 2

[0062] Example 1 was repeated with the exception that the coating of theinert cores with the omeprazole-containing layer was followed firstly bythe application of a first coating layer. A coating solution preparedfrom 5 g of hydroxypropylmethylcellulose, 1.0 g of poloxamer 188, 40 gof deionized water and aqueous 0.5 M sodium dihydrogen phosphatesolution to adjust the pH to about 6.9 was used for this purpose. Thecoating is applied in a fluidized bed coating apparatus. The next inertcoating (second inert coating) and the enteric coating are then appliedto this first inert coating, using the same components, quantities andtechniques as described in Example 1 above.

[0063] The pellets obtained in this way show a superior stability andexcellent bioavailability.

[0064] Where it is stated in this application that (a quantity) of 5 to50 mg of a coating or layer material in 100 mg of water provides a pH ina predefined range, this of course means that to comply with the featureit is sufficient for any quantity of material from the range from 5 to50 mg to provide in 100 mg of water a pH in the defined range. Thus, tocomply with this feature, it is sufficient for example if 5 mg of layermaterial in 100 mg of water provides a pH in the defined range, even ifa different quantity of layer material, such as 10 mg of layer material(or 50 mg of layer material), in 100 mg of water provides a pH which isoutside the defined range.

1. An oral pharmaceutical in the form of pellets comprising abenzimidazole compound of the formula I

in which R1 is hydrogen, methoxy or difluoromethoxy, R2 is hydrogen,methyl or methoxy, R3 is methoxy, 2,2,2-trifluoroethoxy or3-methoxypropoxy, and R4 is hydrogen, methyl or methoxy, comprising (a)an inert core, (b) thereon an active ingredient layer which comprisesthe benzimidazole compound of the formula I mixed with an acidicreacting compound and, where appropriate, pharmaceutically acceptableadjuvants, (c) at least one inert layer and (d) an outer layer which isapplied to the inert layer and which comprises an enteric coating.
 2. Apharmaceutical as claimed in claim 1, in which a first inert layer and asecond inert layer are present, where the first inert layer is appliedto the active ingredient layer, and the second inert layer is applied tothe first inert layer.
 3. A pharmaceutical as claimed in claim 2, inwhich the first inert layer comprises an inert water-soluble polymer,where appropriate an acidic reacting compound and, where appropriate,pharmaceutically acceptable excipients, and the second inert layercomprises a water-soluble polymer and, where appropriate,pharmaceutically acceptable excipients.
 4. A pharmaceutical as claimedin claim 3, in which the first inert layer comprises an acidic reactingcompound.
 5. A pharmaceutical as claimed in any of claims 1 to 4, inwhich the water-soluble polymer comprises hydroxypropylmethylcelluloseand/or hydroxypropyl-cellulose.
 6. A pharmaceutical as claimed in any ofclaims 1 to 5, in which a suspension of the inert core and the activeingredient layer of a pellet in 4 μl of water has a pH in the range from6.5 to 6.95, in particular from 6.6 to 6.95.
 7. A pharmaceutical asclaimed in any of claims 1 to 6, in which the acidic reacting compoundcomprises sodium dihydrogen phosphate.
 8. A pharmaceutical as claimed inany of claims 1 to 7, in which the active ingredient layer and, ifpresent, the first inert layer is free of talc.
 9. A pharmaceutical asclaimed in any of claims 1 to 8, in which the benzimidazole compound ofthe formula I is omeprazole.
 10. A pharmaceutical as claimed in claim 1,comprising (a) an inert core (b) thereon an active ingredient layerwhich consists essentially of omeprazole, hydroxy-propylmethylcelluloseand an acidic reacting compound, where the acidic reacting compound ispresent in an amount such that a suspension of the inert core with theactive ingredient layer in 4 μl of water has a pH in the range from 6.6to 6.95, (c) a first inert layer consisting essentially ofhydroxypropylmethylcellulose, an acidic reacting compound and alubricant, (d) a second inert layer consisting essentially ofhydroxypropylmethylcellulose, talc and a pigment, in particular TiO₂,and (e) an outer layer consisting essentially of an enteric coatingformed from methacrylic acid/alkyl (meth)acrylate copolymer, triethylcitrate and talc.
 11. A pharmaceutical as claimed in claim 10, in whichthe acidic reacting compound is sodium dihydrogen phosphate.
 12. Aprocess for producing a pharmaceutical as claimed in any of claims 1 to11, which comprises the following steps: (i) preparation of an inertcore, (ii) coating of the inert core with a suspension which comprisesthe benzimidazole compound of the formula I and at least one acidicreacting compound and has a pH in the range from 6.5 to 6.95, inparticular from 6.6 to 6.95, (iii) application of at least one inertlayer, (iv) application of an enteric layer.
 13. The process as claimedin claim 12, which comprises the following steps: (i) preparation of aninert core, (ii) coating of the inert core with a suspension whichcomprises the benzimidazole compound of the formula I and at least oneacidic reacting compound and has a pH in the range from 6.5 to 6.95, inparticular from 6.6 to 6.95, (iii) application of a first inert layer,(iv) application of a second inert layer and (v) application of theenteric layer.
 14. The process as claimed in claim 13, where the firstinert layer is applied from a coating solution or suspension which has apH in the range from 6.5 to 6.95, in particular in the range from 6.6 to6.95.
 15. The process as claimed in any of claims 1 to 14, where thelayers are applied by means of a fluidized bed coating apparatus.